Alport syndrome diagnostic criteria

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Diagnostic criteria

The suspicion of Alport’s syndrome should be present when patients present with persistent hematuria of glomerular origin – with dysmorphic RBC and variable hemoglobin content on analysis.[1] However, family history should always be investigated because knowledge of positive family history alone, along with symptoms of Alport’s syndrome, may be diagnostic with up to 80% sensitivity.[1] The definitive diagnosis of Alport’s syndrome can be made by electron microscopy of a kidney biopsy with immunofluorescent assessment.[2]Under microscopy, characteristic lamellated thinned glomerular basement membrane must be identified for proper diagnosis.[1] For diagnostic purposes, at least one COL4A5 mutation or two COL4A3/COL4A4 must be present for X-linked disease or autosomal recessive disease, respectively.

Genetic testing is recommended by expert opinion in 6 conditions[3]:

  • Confirm diagnosis of Alport’s syndrome
  • Identify mode of inheritance
  • Rule out TBMN in patients with persistent hematuria
  • Prognostic outcome according to previously described patterns
  • Provide prenatal diagnosis for at-risk pregnant females
  • To provide embryo pre-implantation genetic diagnosis


Although genetic testing is sensitive up to 90% for the diagnosis of X-linked Alport’s syndrome with heterogeneous COL4A5 mutation, renal impairment with homogeneously mutated COL4A3/COL4A4 should not still not rule out TBMN except after consensus of a multidisciplinary team regarding the clinical manifestations and the histopathological features of the disease per case due to the likelihood of TBMN and concurrent renal impairment due to other etiologies of glomerulonephritis.[1]

The defect of the collagen alpha chains may then be visible using immunofluorescence by H51 monoclonal antibody to NC1 region of the collagen alpha-5 chain to reveal most cases of Alport’s syndrome in affected males and in carrier females.[4][5] If renal biopsy is not possible, the H51 antibody may be used on skin tissue biopsies as well.[4] Auditory lesions are diagnosed using audiometry whose audioscans generate frequencies from 250 Hz to 8000 Hz at a rate of 30s/octave. Audioscans may also identify female carriers of Alport’s syndrome.

In 2013, expert opinion by Savige and colleagues demonstrated a practical approach for the diagnoasis of Alport’s syndrome.[1]

Dignostic Criteria for Diagnosis of Alport's Syndrome
Mandatory Criterion Persistent Hematuria
Optional Criteria Presence of at Least 1 of 4:
  • Positive Family History of Alport's Syndrome
  • Characteristic Clinical Features
  • Characteristic Pathology Findings
  • Genetic Testing

The equivocal or non-characteristic finding of any of the above prompts further work-up until the diagnosis is made or rejected.[1]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F (2013). "Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy.". J Am Soc Nephrol. 24 (3): 364–75. PMID 23349312. doi:10.1681/ASN.2012020148. 
  2. Streeten BW, Robinson MR, Wallace R, Jones DB (1987). "Lens capsule abnormalities in Alport's syndrome.". Arch Ophthalmol. 105 (12): 1693–7. PMID 3689194. 
  3. McCarthy PA, Maino DM (2000). "Alport syndrome: a review.". Clin Eye Vis Care. 12 (3-4): 139–150. PMID 11137428. 
  4. 4.0 4.1 Yoshioka K, Hino S, Takemura T, Maki S, Wieslander J, Takekoshi Y; et al. (1994). "Type IV collagen alpha 5 chain. Normal distribution and abnormalities in X-linked Alport syndrome revealed by monoclonal antibody.". Am J Pathol. 144 (5): 986–96. PMC 1887361Freely accessible. PMID 8178947. 
  5. Kashtan CE, Michael AF (1993). "Alport syndrome: from bedside to genome to bedside.". Am J Kidney Dis. 22 (5): 627–40. PMID 8238007. 

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